Sofalcone derivatives and pharmaceutical uses thereof

Abstract

A series of sofalcone derivatives are provided.SOLUTION: A series of sofalcone derivatives provided by the present invention are, for example, compounds having a structure of formula (I), and have platelet aggregation inhibitory and antithrombotic effects. The sofalcone derivatives of the present invention are TxA2 receptor antagonists, have an inhibitory effect on platelet agglutination, and do not easily affect the hemostatic function. The present invention also provides a method for preparing the sofalcone derivative, and a method for using the sofalcone derivative for preventing or treating thrombotic diseases, or for inhibiting platelet aggregation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a series of sofalcone derivatives, which have platelet aggregation inhibitory and antithrombotic effects, and also to a method of using the sofalcone derivatives for the treatment of thrombotic disorders or the inhibition of platelet aggregation. [Background technology]

[0002] Thromboxane (TxA2) is the major metabolite of arachidonic acid (AA) in platelets. Upon platelet activation, AA is released from the phospholipids in the cell membrane into the cytoplasm, where it is further converted to prostaglandin (PG) G2 / H2 by cyclooxygenase (COX) and then to TxA2 by TxA2 synthase. TxA2 can be released extracellularly and acts on the TxA2 receptor on the platelet membrane, inducing platelet activation and aggregation. Therefore, TxA2 is an important mechanism for enhancing platelet activation. Aspirin inhibits COX, thereby reducing platelet TxA2 synthesis, resulting in its antiplatelet effect. However, aspirin can also inhibit prostaglandin synthesis in other cells, such as by inhibiting the synthesis of prostaglandin I2 (PGI2) in vascular endothelial cells and prostaglandin E2 (PGE2) in gastric cells. Inhibition of PGI2 may counteract the antiplatelet effect of aspirin, and inhibition of PGE2 may be involved in aspirin's induction of peptic ulcers. Therefore, the development of drugs that can antagonize the TxA2 receptor or selectively inhibit the TxA2 synthase may be superior to antiplatelet therapy with aspirin.

[0003] Currently, there are two TxA2 receptor antagonists in clinical use: seratrodast and ramatroban. However, they are only used to treat asthma or allergic rhinitis and have not yet been approved for use in antiplatelet therapy. Picotamide has dual effects as an antagonist of TxA2 synthase and the TxA2 receptor, but its efficacy is relatively low. Therefore, it is not yet widely used in clinical antiplatelet therapy. Therefore, the development of novel TxA2 receptor antagonists is of urgent importance.

[0004] Sofalcone, a member of the chalcone family of compounds, is a synthetically modified derivative of sophoradin, a component of sophora subprostrata root. Sophora subprostrata root is a commonly used traditional Chinese medicine, traditionally used for clearing heat and detoxifying the throat and reducing swelling. Modern research has revealed that sophoradin possesses anti-gastric ulcer properties, and its active ingredient has been identified as sophoradin. Taisho Pharmaceutical of Japan developed sofalcone through synthetic and chemical modification based on the chemical structure of sophoradin, and launched it as an anti-gastric ulcer drug in 1984. Based on its safety and effectiveness, it was approved as an over-the-counter drug in Japan in 1999. Previous studies have demonstrated that sofalcone's anti-gastric ulcer mechanism and its inhibitory activity against 15-hydroxyprostaglandin dehydrogenase (15-PGDH) are related to increased PGE2 levels in gastric tissue. Two of sofalcone's metabolites in humans also have anti-gastric ulcer effects. In addition to its anti-gastric ulcer activity, sofalcone, when used in combination with rabeprazole, amoxicillin, and clarithromycin, enhances the inhibition of Helicobacter pylori infection in gastric tissue, achieving anti-gastritis effects. Recent studies have also demonstrated that sofalcone can not only inhibit the inflammatory response between macrophages and adipocytes, but also reduce the differentiation of preadipocytes into adipocytes, suggesting its potential use in the treatment of obesity and metabolic syndrome. However, there have been no studies to date on sofalcone in cardiovascular disease, particularly on its antiplatelet effects. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention demonstrates that sofalcone has antiplatelet activity and its mechanism is TxA2 antagonist. Based on the chemical structure of sofalcone, the present invention further modifies it to synthesize a series of novel chemical derivatives and measure their antiplatelet aggregation activity. Furthermore, the pharmacophore is optimized based on structure-activity relationships. [Means for solving the problem]

[0006] The sofalcone derivatives disclosed in the present invention can effectively and satisfactorily inhibit platelet aggregation induced by the TxA2 receptor agonist U46619 or collagen. They also exhibit antithrombotic effects in animal experiments, without affecting hemostatic function. Therefore, the sofalcone derivatives disclosed in the present invention can be used as novel platelet inhibitors with effective efficacy and minimal side effects.

[0007] The term "a" or "an" is used herein to describe elements and components of the present invention. The term is merely used to provide a basic concept of the present invention. In addition, the description should be understood to include one or at least one. Furthermore, unless the context clearly dictates otherwise, singular terms include pluralities and plural terms include the singular. When used in conjunction with the word "comprising" in the claims, the term "a" or "an" can refer to one or more.

[0008] As used herein, the term "or" can mean "and / or."

[0009] The present invention provides compounds having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0010] [ka]

[0011] In the formula, R 1is None, H, phenyl (Ph), thiophenyl, furanyl, pyridinyl, bromothiophenyl, thiazolyl, or a phenyl group substituted with X, where X is H, halogen, NO2, NH2, NHAc, O-Ac, O-geranyl, C 1-6 Alkyl group, OC 1-10 Alkyl group, OH, OBn, aminothio group, O-isoprenyl group, O-halobenzyl group, OC 1-6 Alkyloxybenzyl group (OC 1-6 alkyloxybenzyl), OC 1-6 Alkyl-CO-phenyl group, or OC 1-6 Alkyl-COO-C 1-6 is an alkyl group; R 2 None, H, OH, halogen, O-geranyl group, O-isoprenyl group, OC 1-10 Alkyl group, O-Ac, OBn, O-halobenzyl group, OC 1-6 Alkyloxybenzyl group, phenyl-O-isoprenyl group, OC 1-6 Alkyl-CO-phenyl group, or OC 1-6 Alkyl-COO-C 1-6 is an alkyl group; R 3 is OH or OC 1-6 is an alkyl group; n is 1 to 7.

[0012] In specific embodiments, the halogen includes fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and astatine (At). In preferred specific embodiments, the halogen is fluorine or chlorine.

[0013] In another specific embodiment, the C 1-6 Alkyl groups are C 1-3Contains an alkyl group.

[0014] In a specific embodiment, the OC 1-10 The alkyl group is 1-8 In a preferred embodiment, the OC 1-8 The alkyl group is 1-6 In a more preferred embodiment, the OC 1-6 The alkyl group is 1-3 Contains an alkyl group.

[0015] In another specific embodiment, the OC 1-6 Alkyloxybenzyl group is OC 1-3 Contains an alkyloxybenzyl group.

[0016] In a specific embodiment, the OC 1-6 Alkyl-CO-phenyl group is OC 1-3 Contains alkyl-CO-phenyl groups.

[0017] In another specific embodiment, the OC 1-6 Alkyl-COO-C 1-6 The alkyl group is OC 1-3 Alkyl-COO-C 1-3 Contains an alkyl group.

[0018] In a specific embodiment, n is 1 to 5.

[0019] In specific embodiments, the R 1 is phenyl-4-fluoro, the R 2 is H, the R 3 is OH, and n is 5.

[0020] In specific embodiments, the R 1 is a phenyl-4-O-isoprenyl group, the R 2 is an O-isoprenyl group, the R 3 is OH, and n is 3 to 7. In a preferred embodiment, R1 is a phenyl-4-O-isoprenyl group, the R 2 is an O-isoprenyl group, the R 3 is OH, and n is 3.

[0021] The present invention provides compositions comprising a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] The present invention also provides a method of using a composition for preparing an anti-platelet aggregation medicament, the composition comprising a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof.

[0023] The present invention further provides a method for using a composition comprising a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for the prevention or treatment of a disease associated with platelet aggregation.

[0024] The present invention further provides a method for preventing or treating a thrombosis disease, comprising administering to an individual suffering from a thrombotic disease a composition comprising a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof.

[0025] The present invention also provides compounds having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0026] [ka]

[0027] In the formula, R 1 is a phenyl group or a phenyl group substituted with Y, wherein Y is a halogen, OH, O-isoprenyl, or OC 1-6 is an alkyl group; R 2 is H, OH, O-isoprenyl, or OC 1-6 is an alkyl group; R 3 OH,OC1-6 is an alkyl group; n is 1 to 7.

[0028] In a specific embodiment, the halogen is fluorine.

[0029] In another specific embodiment, n is 1-5.

[0030] The present invention provides compositions comprising a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0031] The present invention also provides a method of using a composition for preparing an anti-platelet aggregation medicament, the composition comprising a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0032] The present invention further provides a method for using the composition to prepare a medicament for preventing or treating a disease associated with platelet aggregation, the composition comprising a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof:

[0033] The present invention further provides a method for preventing or treating a thrombotic disorder, comprising administering to an individual suffering from a thrombotic disorder a composition comprising a compound having the structure of Formula (II) or a pharmaceutically acceptable salt thereof.

[0034] The term "pharmaceutically acceptable salt" as used herein refers to a derivative compound obtained by modifying a compound into an acid or alkali and its salt. However, the type of the salt is not limited as long as it is physiologically acceptable.

[0035] As used herein, the term "prevention" refers to suppressing or preventing the symptoms of a particular disease, disorder, condition, or side effect. As used herein, the term "treatment" is meant to include alleviating or eliminating a disease, disorder, or one or more symptoms associated with the disease, disorder, or condition; or alleviating or eradicating the cause of the disease, disorder, or condition itself.

[0036] In this context, the term "individual" may be a mammal, preferably a human.

[0037] In the present invention, the compound having the structure of formula (I) or formula (II) has the effect of antiplatelet aggregation. Furthermore, the compound having the structure of formula (I) or formula (II) can inhibit platelet aggregation activity. Therefore, the compound of the present invention, or a derivative thereof or a pharmaceutically acceptable salt thereof can be used to inhibit platelet aggregation and has antithrombotic activity but does not have a tendency to hemorrhage. Therefore, the present invention provides an antiplatelet drug comprising a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present invention provides a method for inhibiting platelet aggregation, comprising administering to an individual in need thereof a composition comprising a compound having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. Furthermore, the present invention provides a method for preventing or treating a disease associated with platelet aggregation, comprising administering to an individual suffering from the disease associated with platelet aggregation a compound comprising a compound having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof.

[0039] Thrombotic disorders occur in response to injury or other signals that recruit platelets to the injury site. The compounds of formula (I) or formula (II) provided by the present invention can inhibit platelet aggregation, and are therefore applicable to the preparation of therapeutic or prophylactic agents for various platelet aggregation-related diseases or thrombotic disorders. As used herein, the term "thrombotic disorder" refers to a disorder in which the formation or presence of a thrombus in a blood vessel causes or even induces ischemia or infarction in tissues supplied by the blood vessel. In a specific embodiment, the platelet aggregation-related disease or thrombotic disorder includes arterial cardiovascular thrombotic disorders, venous cardiovascular thrombotic disorders, or thrombotic disorders in the cardiac chamber or peripheral circulation. In preferred specific embodiments, the disease associated with platelet aggregation or the thrombotic disorder comprises unstable angina, acute coronary syndrome, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, kidney embolism, pulmonary embolism, or a thrombotic disorder resulting from a medical implant, device, or process that exposes blood to an artificial surface that promotes thrombosis.

[0040] The compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (including sustained-release or timed-release compositions, respectively), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present invention can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly. Thus, the present invention utilizes dosage forms well known to those skilled in the art. The compounds of the present invention can be administered alone, but are generally administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0041] Additionally, the compounds of the present invention can be used to inhibit platelet aggregation in vitro in blood and blood products, e.g., stored or processed from the living body (e.g., for diagnostic or research purposes).

[0042] In the present invention, the compounds of formula (I) or (II) of the present invention can act as TxA2 receptor antagonists and also reduce TxA2 synthesis. At the same time, the compounds of formula (I) or (II) can inhibit the enzymatic activity of COX1 and COX2. Therefore, the compounds of formula (I) or (II) can inhibit platelet activation and aggregation and are antithrombotic. Furthermore, the compounds of formula (I) or (II) do not affect the normal hemostatic function of the individual. Therefore, the present invention provides a method for inhibiting platelet activation and aggregation in an individual without inducing bleeding, comprising administering to the individual a composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The present invention also provides a method for inhibiting thrombus formation in an individual without inducing bleeding, comprising administering to the individual a composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. In the present invention, the individual has a relatively greater risk or is in a relatively dangerous state in thrombus formation compared to a normal individual.

[0043] In summary, the present invention has designed and synthesized a series of novel compounds based on the chemical structure of sofalcone, which have antiplatelet and antithrombotic effects and do not affect hemostatic function in animal experiments. Therefore, the compounds of the present invention can be used as novel antiplatelet drugs or in antiplatelet therapy. [Brief explanation of the drawings]

[0044] [Figure 1] FIG. 1 shows a method for synthesizing a Sofalcone derivative. [Figure 2] Figure 2 shows a method for synthesizing sofalcone derivatives. MeI: iodomethane. [Figure 3] FIG. 3 shows a method for synthesizing sofalcone derivatives. [Figure 4] Figure 4 shows a method for synthesizing sofalcone derivatives. DCM: dichloromethane. KI: potassium iodide. DMF: dimethylformamide. [Figure 5] Figure 5 shows that sofalcone and its derivatives can competitively antagonize U46619-induced platelet aggregation. Figure 5A shows that sofalcone (SFC) can competitively antagonize U46619-induced platelet aggregation. Figure 5B shows that sofalcone derivative 3 can competitively antagonize U46619-induced platelet aggregation. Figure 5C shows that sofalcone derivative 30 can competitively antagonize U46619-induced platelet aggregation. Human platelet suspensions were pretreated with dimethyl sulfoxide (DMSO) or sofalcone (SFC) (Figure 5A), sofalcone derivative 3 (Figure 5B), or sofalcone derivative 30 (Figure 5C), and then various concentrations of U46619 (0.1-10 μM) were added to stimulate platelet aggregation. Data are shown as mean ± standard error of the mean (n = 5). [Figure 6] Figure 6 shows the effects of sofalcone and its derivatives on arachidonic acid (AA)-induced TxB2 and PGE2 production. Figure 6A shows the effects of sofalcone (SFC) and its derivatives on arachidonic acid-induced TxB2 production. Figure 6B shows the effects of sofalcone and its derivatives on arachidonic acid-induced PGE2 production. Human platelet suspensions were pretreated with dimethyl sulfoxide (DMSO) or sofalcone (SFC), sofalcone derivative 3, or sofalcone derivative 30, and then arachidonic acid (100 μM) was added to stimulate the production of arachidonic acid metabolites TxB2 and PGE2. Data are shown as mean ± standard error of the mean (n≧5). *P<0.05, **P<0.01, ***P<0.001 compared with the control group. ASA: aspirin. [Figure 7]Figure 7 shows that sofalcone and its derivatives have anti-arterial thrombotic effects. Figure 7A shows that sofalcone (SFC) has anti-arterial thrombotic effects. Figure 7B shows that sofalcone derivative 17 has anti-arterial thrombotic effects. Mice were orally administered sofalcone (SFC, once daily, a total of four times), derivative 17, or aspirin (ASA) (single dose). Then, thrombosis was induced in the mouse carotid artery with an iron chloride solution, and the time required for the thrombus to occlude the carotid artery (occlusion time) was measured using an ultrasound imaging system. Data are shown as mean ± standard error of the mean (n ≥ 6). Compared with the control group, *P < 0.05, ***P < 0.001. [Figure 8] Figure 8 shows that sofalcone and its derivatives do not affect normal hemostatic function. Figure 8A shows that sofalcone (SFC) does not affect normal hemostatic function. Figure 8B shows that sofalcone derivative 17 does not affect normal hemostatic function. Mice were orally administered sofalcone (SFC, once daily, a total of four times), derivative 17, or aspirin (ASA) (single dose). Then, the tails were cut and the bleeding time of the mice was measured. Data are shown as mean ± standard error of the mean (n≧6). Compared with the control group, ***P<0.001. ns: no significant difference. DETAILED DESCRIPTION OF THE INVENTION

[0045] The following examples are not limiting and merely illustrate various aspects and features of the present invention.

[0046] Materials and Methods 1. Preparation and Analysis of Sofalcone and Its Derivatives Any compound disclosed herein can be prepared by methods commonly used in the relevant fields or by the methods described in the examples of the present invention. The preparation methods of sofalcone and its derivatives of the present invention are shown in Figures 1 to 4.

[0047] 1 to 4 show a general method for synthesizing sofalcone derivatives.

[0048] In the preparation method of the compounds in FIG. 1, the present invention is illustrated by the preparation process of compounds 02, 39, 50, 51 and 61.

[0049] Preparation of Compound 02 The starting material S7 (0.83 g, 3 mmol) was placed in a reaction flask and stirred with ethanol (EtOH) in a stirring bar. 50% KOH was slowly added dropwise and the mixture was allowed to stand for 10 minutes. 4-fluorobenzaldehyde (0.37 g, 3 mmol), pre-dissolved in ethanol, was then added dropwise to the reaction flask and stirred at room temperature for 12-16 hours. After the reaction was determined to be complete by thin-layer chromatography (TLC), the precipitate of a solid suspension was confirmed. The solvent was removed using a vacuum concentrator, and 200 mL of water was added. The mixture was then acidified with 6N hydrochloric acid (HCl) to a pH of 4. The crude product was then extracted with ethyl acetate (EA). The product was then purified by column chromatography using a 1:1 EA:n-hexane (hex) mixture as the eluent. Compound 02 was obtained by recrystallization from ethanol.

[0050] 1 H NMR(400MHz,CDCl3)δ7.67-7.72(d,J=16Hz,1H,Ar-H),7.67-7.65(dd,J=8Hz, 1H,Ar-H),7.61-7.57(m,1H,Ar-H),7.54(s,1H),7.48-7.44(m,1H,Ar-H),7.38 -7.32(m,1H,Ar-H),7.19-7.08(m,1H,Ar-H),7.04-7.01(m,1H),6.97(s,1H), 6.95(s,1H),4.08(m,4H),2.15(m,2H),1.71(m,2H),1.56(m,2H),1.27(m,2H).

[0051] Preparation of Compound 39 Compound 02 (1.12 g, 3 mmol) was placed in a reaction flask, and the resulting mixture was stirred with a stir bar in ethanol. 3 mL of concentrated hydrochloric acid was slowly added dropwise, and the mixture was refluxed for 2 hours. The reaction mixture was then analyzed by TLC. After determining the reaction was complete, the solvent was removed using a vacuum evaporator. 200 mL of water was added, and the crude product was extracted with EA. The resulting product was then purified by column chromatography using EA:n-hexane (hex) = 1:1 as the eluent to obtain compound 39.

[0052] 1 H NMR(400MHz,CDCl3)δ7.67-7.72(d,J=16Hz,1H,Ar-H),7.67-7.65(dd,J=8Hz,1H, Ar-H),7.61-7.57(m,1H,Ar-H),7.54(s,1H),7.48-7.42(m,1H,Ar-H),7.35-7.32 (m,1H,Ar-H),7.19-7.06(m,1H,Ar-H),7.04-7.01(m,1H),6.97(s,1H),6.95(s,1 H),4.08(m,4H),2.13(m,2H),1.79(m,2H),1.54(m,2H),1.26(m,2H),1.22(m,3H).

[0053] Preparation of Compound 50 Compound 02 (1.12 g, 3 mmol) was placed in a reaction flask and palladium carbon catalyst Pd / C (0.11 g, 1 mmol) was added. The reaction flask was evacuated and subjected to a vacuum. Methanol (MeOH) was used as the solvent, followed by hydrogen gas. The reaction was allowed to proceed at room temperature for 1-3 hours. After TLC analysis showed the reaction was complete, the mixture was filtered under reduced pressure through a filter packed with Celite, and the solvent was removed using a vacuum concentrator. The resulting mixture was then purified by column chromatography using EA:n-hexane (hex) = 1:5 as the eluent to obtain compound 50.

[0054] 1H NMR(400MHz,CDCl3)δ7.73(d,J=16Hz,1H,Ar-H),7.64(dd,J=8Hz,1H,Ar-H),7.61-7.56(m,1H,Ar-H),7.52(s,1H),7.48-7.43(m ,1H,Ar-H),7.37-7.32(m,1H,Ar-H),7.18-6.95(m,3H,Ar-H),4.05(m,4H),2.19(m,2H),1.81(m,2H),1.56(m,2H),1.46(m,2H).

[0055] Preparation of Compound 51 The starting material S7 (0.83 g, 3 mmol) was placed in a reaction flask with ethanol as the solvent, and a stir bar was added. 50% potassium hydroxide (KOH) was slowly added dropwise and the mixture was allowed to stand for 10 minutes. Thiophene-2-carboxaldehyde (0.34 g, 3 mmol), pre-dissolved in ethanol, was then added dropwise to the reaction flask and the mixture was stirred at room temperature for 12-16 hours. After the reaction was determined to be complete by TLC, the precipitate of a solid precipitate was confirmed. The solvent was removed using a vacuum concentrator, and 200 mL of water was added. The mixture was then acidified with 6N HCl to a pH of 4. The crude product was extracted with ethyl acetate (EA). The product was then purified by column chromatography using a 1:1 EA:n-hexane (hex) mixture as the eluent. Compound 51 was obtained by recrystallization from ethanol.

[0056] 1 H NMR(400MHz,CDCl3)δ7.78-7.75(d,J=12Hz,1H,Ar-H),7.67-7.63(dd,J=16Hz,1H,Ar-H),7.46-7.42(m,1H,Ar-H),7.30(s,1H),7.26-7.28(d,1H,Ar- H),7.07-7.04(m,1H,Ar-H),7.02(t,1H,Ar-H),6.96-6.74(d,J=8.1H,Ar- H),4.056(m,2H),1.81-1.82(m,2H),1.63-1.61(m,2H),1.53-1.51(m,2H).

[0057] Preparation of Compound 61 Compound 51 (1.12 g, 3 mmol) was placed in a reaction flask, and the mixture was stirred with a stir bar in ethanol. 3 mL of concentrated hydrochloric acid was slowly added dropwise, and the mixture was heated under reflux for 2 hours. After TLC showed the reaction was complete, the solvent was removed using a vacuum evaporator. 200 mL of water was added, and the crude product was extracted with EA. Compound 61 was then purified by column chromatography using EA:n-hexane (hex) = 1:1 as the eluent.

[0058] 1 H NMR(400MHz,CDCl3)δ7.78-7.75(d,J=16Hz,1H,Ar-H),7.67-7.65(dd,J=8Hz,1H, Ar-H),7.74-7.41(m,1H,Ar-H),7.37-7.36(d,J=16Hz,1H,Ar-H),7.32(s,1H),7. 28(s,1H),7.06-7.05(m,1H),7.02-6.98(m,1H),6.95-6.93(d,J=Hz,1H),4.01-4 .02(m,4H),2.1-2.17(m,2H),1.86-1.79(m,2H),1.65-1.47(m,4H),1.22(m,3H).

[0059] In the preparation method of the compounds of FIG. 2, the present invention is illustrated by the preparation process of compounds 74 and 76.

[0060] Preparation of compound 74 Process 1: Starting material S13 (0.92 g, 3 mmol) is placed in a reaction flask with ethanol as the solvent. A stir bar is added and the mixture is stirred. 50% KOH is slowly added dropwise and the mixture is left to stand for 10 minutes. S14 (0.57 g, 3 mmol), previously dissolved in ethanol, is then added dropwise to the reaction flask and the mixture is stirred at room temperature for 12-16 hours. After the reaction is complete, a solid precipitate is observed by TLC. The solvent is removed using a vacuum concentrator, 200 mL of water is added, and the mixture is acidified with 6N HCl to a pH of 4. The crude product is then extracted with ethyl acetate (EA). The product is then purified by column chromatography using EA:n-hexane (hex) = 1:1 as the eluent. Recrystallization from ethanol yields the compound sofalcone.

[0061] Step 2: Sofalcone (1.4 g, 3 mmol) is placed in a reaction flask with methanol as the solvent. After stirring with a stir bar, 3 mL of concentrated hydrochloric acid is slowly added dropwise and the mixture is heated to reflux for 1-2 hours. After confirming complete reaction by TLC, the solvent is removed using a vacuum concentrator. An additional 200 mL of water is added, and the crude product is extracted with EA. This is then purified by column chromatography to obtain compound 69.

[0062] Step 3: Compound 69 (0.98 g, 3 mmol) was placed in a reaction flask and palladium-carbon catalyst Pd / C (0.11 g, 1 mmol) was added. The reaction flask was evacuated, and methanol was used as the solvent. Hydrogen gas was then introduced, and the reaction was allowed to proceed at room temperature for 1-3 hours. After TLC showed the reaction was complete, the mixture was filtered under reduced pressure through a filter filled with Celite, and the solvent was removed using a vacuum concentrator. Compound 72 was then purified by column chromatography to give the product.

[0063] Step 4: Compound 72 (0.99 g, 3 mmol) and potassium carbonate (2.1 g, 15 mmol) were placed in a reaction flask, and the mixture was stirred with acetone. Isoprenyl bromide (1.88 g, 12 mmol) was then slowly added dropwise, and the mixture was allowed to react at room temperature for 12-16 hours. After TLC showed the reaction was complete, the solvent was removed using a vacuum concentrator. 200 mL of water was added, and the mixture was neutralized with 6N HCl to a pH of 7. The crude product was extracted with EA. Compound 74 was then purified using a 1:5 mixture of EA and n-hexane (hex) as the eluent.

[0064] 1 H NMR(400MHz,CDCl3)δ7.83-7.81(d,J=8Hz,1H,Ar-H),7.16-7.14(d,J=8Hz,2H,Ar-H),6.84-6.82(d,J=8Hz,2H,Ar-H),6.58-6.56(d,1H,Ar-H), 5.51-5.44(m,2H),4.66(s,2H),4.54-4.46(dd,J=32Hz,4H),3.73(s,3H ),3.36-3.43(t,2H),2.96(t,3H),1.81-1.78(m,6H),1.75-1.73(m,6H).

[0065] Preparation of Compound 76 Compound 74 (1.4 g, 3 mmol) was placed in a reaction flask, and the mixture was stirred with a stirring bar in methanol. 50% KOH was slowly added dropwise and the mixture was allowed to react at room temperature for 1-2 hours. After confirming complete reaction by TLC, the solvent was removed using a vacuum concentrator. 200 mL of water was added, and the mixture was acidified with 6N HCl to pH 4. The crude product was extracted with EA. Compound 76 was then purified by column chromatography using EA:n-hexane (hex) = 1:5 as the eluent.

[0066] 1H NMR(400MHz,CDCl3)δ7.72-7.70(d,J=8Hz,1H,Ar-H),7.12-7.11(d,J=4Hz,2H,Ar-H),6.84-6.82(d,J=16Hz,2H,Ar -H),6.59-6.44(m,2H,Ar-H),5.48-5.44(m,2H),4.69-4.46(m,6H),3.21(s,2H),2.96(s,2H),1.80-1.73(m,12H).

[0067] In the preparation method of the compound of FIG. 3, the present invention is illustrated by the preparation process of compound 98.

[0068] Preparation of Compound 98 The starting material S1 (1.23 g, 4 mmol) was placed in a reaction flask with ethanol as the solvent, and a stir bar was added. 50% KOH was slowly added dropwise and the mixture was allowed to stand for 10 minutes. Terephthalaldehyde (0.27 g, 2 mmol), previously dissolved in ethanol, was then added dropwise to the reaction flask and the mixture was stirred at room temperature for 12-16 hours. After the reaction was determined to be complete by TLC, the precipitate of a solid precipitate was confirmed. The solvent was removed using a vacuum concentrator, and 200 mL of water was added. The mixture was then acidified with 6N HCl to a pH of 4. The crude product was extracted with ethyl acetate (EA). The product was then purified by column chromatography using EA:n-hexane (hex) = 1:1 as the eluent. Compound 98 was obtained by recrystallization from ethanol.

[0069] 1 H NMR(400MHz,DMSO)δ8.11-8.08(d,J=12Hz,4H,Ar-H),7.81(s,4H,Ar-H),6.67-6.49(m,2H) ,5.45-5.42(m,2H),4.87(m,4H),4.62-4.61(d,J=4,4H),1.75-1.73(m,12H),2.96(s,2H).

[0070] In the preparation method of the compounds of FIG. 4, the present invention is illustrated by the preparation process of compounds 83 and 84.

[0071] Preparation of Compound 83 Compound 69 (0.98 g, 3 mmol) and potassium carbonate (2.1 g, 15 mmol) were placed in a reaction flask, and acetone was used as the solvent. Ethyl 2-bromoacetate (1.00 g, 6 mmol) was slowly added dropwise, and the mixture was allowed to react at room temperature for 12 to 16 hours. After TLC showed the reaction was complete, the solvent was removed using a vacuum concentrator. 200 mL of water was added, and the mixture was neutralized with 6N HCl to a pH of 7. The crude product was extracted with EA. Compound 83 was then purified by column chromatography using EA:n-hexane (hex) = 1:5 as the eluent.

[0072] 1 H NMR(400MHz,DMSO)δ7.72-7.59(m,6H,Ar-H),7.00-6.98(d,J=8Hz,2H,Ar-H),6.71-6.7 0(m,1H,Ar-H),5.01(s,2H),4.89-4.85(d,J=16Hz,4H),3.72(s,3H),1.25-1.20(m,6H).

[0073] Preparation of Compound 84 Compound 83 (1.5 g, 3 mmol) was placed in a reaction flask with acetone as the solvent and a stir bar added. 50% KOH was slowly added dropwise and the mixture was allowed to react at room temperature for 1-2 hours. After confirming complete reaction by TLC, the solvent was removed using a vacuum concentrator. 200 mL of water was added, and the mixture was acidified with 6N HCl to pH 4. The crude product was extracted with EA. Compound 84 was then purified by column chromatography using EA:n-hexane (hex) = 1:1 as the eluent.

[0074] 1H NMR(400MHz,DMSO)δ7.89-7.85(d,J=16Hz,1H,Ar-H),7.75-7.23(d,J=8Hz,1H,Ar-H),7.68-7.62(t,2H,Ar-H),7.58(s,1H,Ar-H),6 .96-6.94(d,J=8Hz,1H,Ar-H),6.70-6.69(d,J=4Hz,6H,Ar-H),6.65-6.63(dd,J=8Hz,1H),4.90(s,2H),4.79-7.75(d,J=16Hz,4H).

[0075] 2. Preparation of Human Platelet Suspension Blood samples are collected from healthy donors and anticoagulated with acid-citrate-dextrose (ACD) solution, and platelets are extracted from the blood samples by centrifugation and washed to remove residual plasma, preparing a platelet suspension.

[0076] 3. Measurement of platelet aggregation This experiment was measured using a platelet aggregation measuring device (Chrono-Log Co., Havertown, PA, USA). The test compound was added to the platelet suspension and incubated at 37°C with stirring (1200 rpm) for 3 minutes. Platelet aggregation was then induced by adding the platelet stimulant U46619 or collagen, and the measurement time was 5 minutes. Regarding the measurement principle of platelet aggregation, when platelets undergo aggregation due to the stimulant, the light transmittance of the platelet suspension increases. The platelet aggregation rate can be obtained by calculating the change in light transmittance before and after the platelet suspension is stimulated.

[0077] 4. Measurement of TxB2 and PGE2 Content in Platelets The test compound was added to the platelet suspension and incubated at 37°C with stirring (1200 rpm) for 3 minutes. Arachidonic acid (AA) (100 μM) was then added and incubated for 4 minutes. Finally, EDTA (5 mM) was added to stop the reaction. The samples were centrifuged at 4°C and 13,000 rpm for 1 minute, and the supernatant was collected. The concentrations of TxB2 and PGE2 in the supernatant were measured using enzyme immunoassay kits (TxB2 ELISA kit and PGE2 ELISA kit; Cayman Chemical Company), respectively.

[0078] 5. Measurement of COX1 and COX2 enzyme activity COX1 and COX2 enzyme activity was analyzed using a human COX inhibitor screening kit (Cayman Chemical Company). The test compound was incubated with human recombinant COX1 or COX2 enzyme and heme at 37°C for 15 minutes, followed by the addition of AA (10 μM) for 2 minutes. Subsequently, stannous chloride was added to reduce the COX reaction product PGH2 to PGF2α. Finally, the PGF2α content in the sample was measured using an enzyme immunoassay, and the inhibition rate was calculated.

[0079] 6. Ferric Chloride-Induced Murine Carotid Artery Thrombosis Test This test utilizes the fact that iron chloride induces vascular damage and further thrombosis, and evaluates the antithrombotic effect of the test compound. The test compound is orally administered to BALB / c mice approximately 6 to 8 weeks old. After that, the mice are anesthetized with isoflurane, and the right carotid artery is exposed by surgery. A filter paper (2 x 4 mm) containing 8.5% iron chloride is inserted into the mouse. 2) was attached to the right carotid artery for 3 minutes. After removing the filter paper, the remaining iron chloride was wiped away with a cotton ball moistened with saline, and blood flow in the right carotid artery was measured using an ultrasound imaging system (VEVO 2100 system; VisualSonics) combined with a Doppler flow probe (MS400, 18-38 MHz). Vascular occlusion was determined when blood flow ceased for 1 minute. Failure of blood flow to cease after 30 minutes was considered the endpoint of the experiment.

[0080] 7. Mouse Bleeding Test The present invention utilizes a method in which the end of a mouse's tail is resected to induce bleeding, and the effect of a test compound on normal hemostasis is evaluated. The test compound is orally administered to approximately 6-8 week-old BALB / c mice. The mice are then anesthetized with isoflurane, and a 2 mm section of the tail is resected. The mouse's tail is then immersed in saline at 37°C, and the bleeding time is measured. The bleeding time is determined by the time required for bleeding to completely stop after resecting the mouse's tail. If bleeding does not stop after 15 minutes, this is considered the experimental endpoint.

[0081] 8.Statistical analysis The experimental results of the present invention are expressed as mean ± standard error of the mean. Statistical significance was calculated using one-way analysis of variance (One-way ANOVA) in GraphPad Prism software. A p-value of <0.05 was considered to have statistical significance.

[0082] result 1. Antiplatelet aggregation effects of sofalcone derivatives In the present invention, the sofalcone derivatives prepared in Figures 1 to 4 are divided into two types: (A) The first type of compound has the formula (I).

[0083] [ka]

[0084] The compounds having the formula (I) include derivatives 1 to 48, 51 to 71, 77 to 99, and 101 to 114. (B) The second type of compounds has the formula (II).

[0085] [ka]

[0086] Compounds having the formula (II) include derivatives 49, 50, 72-76, 100, 115, and 116.

[0087] Table 1 shows that sofalcone (SFC) derivatives can effectively inhibit platelet aggregation induced by the TxA2 agonist U46619 or collagen, and the effect is superior to that of clinical drugs aspirin and seratrodast.

[0088] [Table 1]

[0089] JPEG2026001671000006.jpg208167

[0090] JPEG2026001671000007.jpg210166

[0091] JPEG2026001671000008.jpg211170

[0092] JPEG2026001671000009.jpg212169

[0093] 2. Sofalcone and its derivatives competitively antagonize U46619-induced platelet aggregation Figures 5A to 5C show that sofalcone and its derivatives 3 and 30 can inhibit platelet aggregation induced by U46619 (100 μM) in human platelet suspensions. Human platelet suspensions were pretreated with dimethyl sulfoxide (DMSO), sofalcone (20 μM and 50 μM), and sofalcone derivatives 3 or 30 (both 0.2 μM and 0.5 μM), and then platelet aggregation was stimulated by adding different concentrations of U46619 (0.1 to 10 μM). In the presence of sofalcone and its derivatives, the U46619 concentration-platelet aggregation response curve shifted parallel to the right, but the maximum platelet aggregation value was not significantly affected. Based on these results, sofalcone and its derivatives 3 and 30 can competitively antagonize the TxA2 receptor.

[0094] 3. Effects of sofalcone and its derivatives on AA metabolites in human platelets 6A and 6B show the effects of sofalcone and its derivatives 3 and 30 on the production of TxB2 (a stable metabolite of TxA2) and PGE2 induced by arachidonic acid (AA) (100 μM) in human platelet suspensions. Sofalcone and its derivative 30 do not inhibit the production of platelet TxB2 and PGE2. However, derivative 3, similar to aspirin, can inhibit the production of both TxB2 and PGE2. Based on the above results, it can be seen that derivative 3 not only has TxA2 receptor antagonistic activity, but also reduces the synthesis of TxA2.

[0095] 4. Effects of sofalcone derivatives on human recombinant COX1 and COX2 Table 2 shows that Derivative 3 can inhibit the enzymatic activity of human recombinant COX1 and COX2 in a dose-dependent manner, and has a favorable inhibitory effect on COX1. Based on the above results, it can be seen that Derivative 3 reduces the synthesis of platelet TxA2 by inhibiting COX1.

[0096] [Table 2]

[0097] 5. Antithrombotic effects of sofalcone and its derivatives in animal models Figures 7A and 7B show that mice were orally administered sofalcone (50 mg / kg daily for 4 days) or derivative 17 (the potassium salt of derivative 30) (single dose of 10 or 25 mg / kg). In a FeCl3-induced carotid artery thrombosis model, the carotid artery occlusion time was significantly prolonged, demonstrating its antithrombotic effect in vivo. In comparison, aspirin (ASA) (25 mg / kg) also prolonged the carotid artery occlusion time.

[0098] 6. Effects of sofalcone and its derivatives on bleeding time in animal models Figures 8A and 8B show that administration of sofalcone (50 mg / kg daily for 4 days) or derivative 17 (potassium salt of 30) (single dose of 10 or 25 mg / kg) by gavage to mice did not affect the bleeding time after tail amputation, demonstrating that they do not inhibit normal hemostatic function. In comparison, aspirin (ASA) (25 mg / kg) significantly prolonged the bleeding time after tail amputation in mice.

[0099] It is properly described that the present invention can be practiced under important conditions or limitations not specifically disclosed herein. The terms used in the description are not limiting. Expressions and descriptions using these terms and any other equivalents are not different, but it should be recognized that the rights within the present invention can be modified. Therefore, although the present invention has been described in examples and other situations, the contents disclosed herein can be modified and changed by those skilled in the art, and such modifications and changes are considered to be within the scope of the present invention.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 In the formula, R １ is no group, H, a phenyl group, a thiophenyl group, a furanyl group, a pyridinyl group, a bromothiophenyl group, a thiazolyl group, or a phenyl group substituted with X, and X is H, a halogen, NO ２ , N.H. ２ , NHAc, O-Ac, O-geranyl group, C １－６ Alkyl group, O-C １－１０ Alkyl group, OH, OBn, aminothio group, O-isoprenyl group, O-halobenzyl group, O—C １－６ Alkyloxybenzyl group, O—C １－６ alkyl-CO-phenyl group, or O—C １－６ Alkyl-COO-C １－６ is an alkyl group; R ２ No, H, OH, halogen, O-geranyl group, O-isoprenyl group, O-C １－１０ Alkyl group, O-Ac, OBn, O-halobenzyl group, O-C １－６ Alkyloxybenzyl group, phenyl-O-isoprenyl group, O—C １－６ alkyl-CO-phenyl group, or O—C １－６ Alkyl-COO-C １－６ is an alkyl group; R ３ is OH or O-C １－６ is an alkyl group; A compound or a pharmaceutically acceptable salt thereof, wherein n is 1 to 7.

2. The R １ is phenyl-4-fluoro, ２ is H, said R ３ 2. The compound of claim 1, wherein n is 5, or a pharmaceutically acceptable salt thereof.

3. The R １ is a phenyl-4-O-isoprenyl group, ２ is an O-isoprenyl group, ３ The compound according to claim 1, wherein is OH, and n is 3 to 7, or a pharmaceutically acceptable salt thereof.

4. The R １ is a phenyl-4-O-isoprenyl group, ２ is an O-isoprenyl group, ３ 2. The compound of claim 1, wherein n is 3, or a pharmaceutically acceptable salt thereof.

5. 10. A method of using a composition for preparing an antiplatelet aggregation medicament, wherein the composition comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. A method for using a composition for preparing a medicament for preventing or treating a disease associated with platelet aggregation, the composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. 7. The method of claim 6, wherein the disease associated with platelet aggregation comprises unstable angina, acute coronary syndrome, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral arterial occlusive disease, venous thromboembolism, thrombophlebitis, arterial embolism, renal embolism, pulmonary embolism, or thrombotic disorders caused by medical implants, devices, or processes that expose blood to artificial surfaces that promote thrombosis.

8. A compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 In the formula, R １ is a phenyl group or a phenyl group substituted with Y, and Y is a halogen, OH, an O-isoprenyl group, or an O—C １－６ is an alkyl group; R ２ is H, OH, an O-isoprenyl group, or O—C １－６ is an alkyl group; R ３ OH, O-C １－６ is an alkyl group; A compound or a pharmaceutically acceptable salt thereof, wherein n is 1 to 7.

9. 10. A method of using a composition for preparing an antiplatelet aggregation medicament, wherein the composition comprises the compound of claim 8 or a pharmaceutically acceptable salt thereof.

10. A method of using a composition for preparing a medicament for preventing or treating a disease associated with platelet aggregation, the composition comprising a compound of claim 8 or a pharmaceutically acceptable salt thereof.

11. 11. The method of claim 10, wherein the disease associated with platelet aggregation comprises unstable angina, acute coronary syndrome, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral arterial occlusive disease, venous thromboembolism, thrombophlebitis, arterial embolism, renal embolism, pulmonary embolism, or thrombotic disorders caused by medical implants, devices, or processes that expose blood to artificial surfaces that promote thrombosis.

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